WO2003065992A2 - Treating benign prostate hyperplasia with sarms - Google Patents

Treating benign prostate hyperplasia with sarms Download PDF

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Publication number
WO2003065992A2
WO2003065992A2 PCT/US2003/003447 US0303447W WO03065992A2 WO 2003065992 A2 WO2003065992 A2 WO 2003065992A2 US 0303447 W US0303447 W US 0303447W WO 03065992 A2 WO03065992 A2 WO 03065992A2
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Prior art keywords
sarm
compound
nhcor
conhr
alkyl
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PCT/US2003/003447
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English (en)
French (fr)
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WO2003065992A3 (en
Inventor
Mitchell S. Steiner
Karen A. Veverka
Duane D. Miller
James T. Dalton
Kiwon Chung
Wenqing Gao
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Gtx, Inc.
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Priority to MXPA04007639A priority Critical patent/MXPA04007639A/es
Priority to AT03737647T priority patent/ATE518537T1/de
Application filed by Gtx, Inc. filed Critical Gtx, Inc.
Priority to AU2003216174A priority patent/AU2003216174C1/en
Priority to JP2003565418A priority patent/JP4677516B2/ja
Priority to CA002475108A priority patent/CA2475108A1/en
Priority to EA200401043A priority patent/EA013399B1/ru
Priority to YU69704A priority patent/RS69704A/sr
Priority to DK03737647.2T priority patent/DK1480634T3/da
Priority to EP03737647A priority patent/EP1480634B1/de
Priority to BRPI0307699-7A priority patent/BRPI0307699A2/pt
Priority to KR1020047012236A priority patent/KR101032661B1/ko
Priority to CN038078007A priority patent/CN1646115B/zh
Publication of WO2003065992A2 publication Critical patent/WO2003065992A2/en
Publication of WO2003065992A3 publication Critical patent/WO2003065992A3/en
Priority to IL163380A priority patent/IL163380A/en
Priority to HR20040793A priority patent/HRP20040793A2/xx
Priority to HK05101488.2A priority patent/HK1068103A1/xx
Priority to AU2009201084A priority patent/AU2009201084A1/en
Priority to IL202675A priority patent/IL202675A/en
Priority to HR20100067A priority patent/HRP20100067A2/hr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens

Definitions

  • This invention relates to the prevention and/or treatment of benign prostate hyperpiasia (BPH). More particularly, this invention relates to a method of treating, preventing, suppressing, inhibiting, or reducing benign prostate hyperpiasia in a male subject suffering from benign prostate hyperpiasia, comprising administering to said subject a selective androgen receptor modulator and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or mixtures thereof.
  • Benign prostate hyperpiasia is a nonmalignant enlargement of the prostate gland.
  • BPH is the most common non-malignant proliferative abnormality found in any internal organ and the major cause of morbidity in the adult male.
  • the initial development of BPH begins as early as 30 to 40 years of age and the prevalence is approximately 10% for that age group. With advancing age, the prevalence of BPH increases progressively. BPH occurs in over 75% of men over 50 years of age, reaching 88% prevalence by the ninth decade.
  • the general aging of the United States population, as well as increasing life expectancies, is anticipated to contribute to the continued growth in the number of BPH sufferers.
  • BPH frequently results in a gradual squeezing of the portion of the urethra which traverses the prostate (prostatic urethra). This causes patients to experience a frequent urge to urinate because of incomplete emptying of the bladder and a burning sensation or similar discomfort during urination.
  • the obstruction of urinary flow can also lead to a general lack of control over urination, including difficulty initiating urination when desired, as well as difficulty of urinary retention because bladder outlet obstruction and a uncontrollable urinary continence due to residual urine , a condition known as overflow urinary incontinence.
  • the first component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of urine from the bladder.
  • the second component is due to increased smooth muscle tone of the bladder neck and the prostate itself, which interferes with emptying of the bladder and is regulated by ⁇ 1 adrenergic receptors ( ⁇ 1-Ars).
  • DHT dihydrotestosterone
  • Testosterone is converted by 5-aIpha-reductase (5 ⁇ -reductase) to DHT, which is about five times more potent than testosterone due to its greater binding affinity to the androgen receptor.
  • DHT binds to cytoplasmic receptors in the prostate, where it initiates RNA and DNA synthesis. This action, in turn, induces protein synthesis and abnormal growth of the prostate.
  • 5- ⁇ reductase There are two isoforms of 5- ⁇ reductase in mammals, particularly humans.
  • the type 1 isoenzyme is highly expressed in liver and skin, has a lower affinity for testosterone, and behaves more-like a catabolic reagent.
  • the type 2 isoenzyme is mainly expressed in androgen target tissues, has higher affinity for testosterone, and amplifies the androgenic effects of testosterone by converting it into DHT.
  • Androgen deprivation can decrease the obstructive symptoms of BPH.
  • current clinical evidence indicates that inhibition of 5 ⁇ -reductase reverses the symptoms of BPH in human males (Strauch, G. et al., Eur. Urol., Vol. 26, pp. 247-252 (1994); Rhodes, L. et al., Prostate, Vol. 22, pp. 43-51 (1993)).
  • 5 ⁇ -reductase activity appears to be higher in cells obtained from BPH tissue than from normal prostate tissue. (Bone, K., The European Journal of Herbal Medicine, Vol. 4(1), pp. 15-24 (1998)).
  • Surgical intervention is the currently accepted treatment for BPH and is generally reserved for patients with intolerable symptoms or those with significant potential symptoms if treatment is withheld.
  • Surgical therapy includes including transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP), and open surgery.
  • Drugs useful for the treatment of BPH are designed to treat prostate enlargement, which characterizes BPH, by shrinking the prostate or by inhibiting or slowing the growth of prostate cells.
  • Finasteride Proscar. RTM., Merck
  • Finasteride is one such therapy which is indicated for the treatment of symptomatic BPH.
  • Finasteride is a competitive inhibitor of the enzyme 5 ⁇ -reductase type 2, which is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland.
  • Other drugs are designed to relax the muscles in the prostate P-4738-PC and bladder neck to relieve urethral obstruction.
  • Terazosin (Hytrin, Abbott) is an adrenergic receptor blocking agent ( ⁇ 1-AR blockers) which acts by decreasing the smooth muscle tone within the prostate gland, urethra and bladder.
  • BPH if left unabated, can have dire health consequences. BPH can lead to acute urinary retention (complete inability to urinate), serious life threatening urinary tract infections and urosepsis and permanent bladder and kidney damage.
  • innovative approaches are urgently needed at both the basic science and clinical levels to treat BPH. The development of new non-invasive therapeutic approaches could result in a substantial increase in the number of BPH patients who elect to receive therapy. The present invention is directed to satisfying this need.
  • this invention relates to a method of treating a male subject suffering from benign prostate hyperpiasia, comprising the step 'of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of preventing, suppressing, inhibiting or reducing the incidence of benign prostate hyperpiasia in a male subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
  • SARM selective androgen receptor modulator
  • this invention relates to a method of treating a subject suffering from hair loss, comprising the step of administering to said subject a therapeutically effective amount of a 5- ⁇ reductase enzyme inhibitor, wherein said inhibitor is a selective androgen receptor modulator (SARM) and/or P-4738-PC its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
  • SARM selective androgen receptor modulator
  • This invention further relates to a method of inhibiting a 5- ⁇ reductase enzyme, comprising contacting the enzyme with an effective 5- ⁇ reductase inhibitory amount of a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
  • SARM selective androgen receptor modulator
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor, is a compound represented by the structure of formula I.
  • G is O or S
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • T is OH, OR, -NHCOCH 3 , or
  • NHCOR Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, S0 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: P-4738-PC
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
  • R1 is CH 3l CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 .
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula II.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • Z is NO 2) CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 ,
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula III.
  • X is a bond, O, CH 2 , NH, Se, PR, NO dr NR; G is O or S;
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 ,
  • A is a ring selected from:
  • B is a ring selected from:
  • Q Nx Q ' wherein A and B cannot simultaneously be a benzene ring;
  • Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN CR 3 or SnR 3 ;
  • Qi and Q 2 are independently of each other a hydrogen, alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR NHSO2CH3, NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR,
  • Q 3 and Q 4 are independently of each other a hydrogen, alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3l NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCFs, NHCSR NHS0 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;
  • Wi O, NH, NR, NO or S;
  • W 2 is N or NO.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula IV.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • G is O or S
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
  • R-i is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 , NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, NR 2 , SR;
  • R 3 is F, Cl, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 , . SnR 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • Z is NO 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS0 2 CH 3 , NHS0 2 R, OH, OR, COR, OCOR, OS0 2 R, S0 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula V.
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, N0 2) NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, NR 2 , SR;
  • R 3 is F, Cl, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 , SnR 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF2CF 3 , aryl, phenyl, halogen, alkenyl or OH;
  • Z is N0 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, alkyl, halogen, CF 3) CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3l NHCSR NHS0 2 CH 3 , P-4738-PC
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula VI.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula VII.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula VIII.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula IX.
  • the SARM is an androgen receptor agonist. In another embodiment, the SARM is an androgen receptor antagonist. In another embodiment, the SARM is an inhibitor of 5 ⁇ -reductase enzyme. In another embodiment, the SARM is a competitive inhibitor of 5 ⁇ -reductase enzyme.
  • the 5- ⁇ reductase enzyme is a type 1 5- ⁇ reductase P-4738-PC enzyme. In another embodiment, the 5- ⁇ reductase enzyme is a type 2 5- ⁇ reductase enzyme. In another embodiment, the 5- ⁇ reductase enzyme is a testosterone 5- ⁇ reductase enzyme, i.e. the enzyme which converts testosterone
  • This invention provides in one embodiment a method of blocking the ability of DHT to induce hyperpiasia comprising contacting the Androgen
  • Receptor with any one or more of Compound l-Vl or a composition comprising any one or more of Compound l-Vl , thereby blocking the ability of DHT to induce hyperpiasia.
  • the compound is Compound II.
  • the compound is Compound VI.
  • This invention provides in one embodiment a method of blocking the ability of DHT to induce hyperpiasia comprising contacting the Androgen Receptor with any one or more of Compound I-VI or a composition comprising any one or more of Compound I-VI, thereby blocking the ability of DHT to induce hyperpiasia.
  • the compound is Compound II.
  • the compound is Compound VI.
  • Compound I-VI is a partial agonist and selective agonist that upon contact with the Androgen Receptor or by administration in a subject prevents mitogenic action of Testosterone and DHT by blocking the ability of endogenous ligands to bind to the receptor.
  • the compound is Compound II.
  • the compound is Compound VI.
  • the Compound I-VI prevents recruitment of co- activators or co-regulators of androgen-responsive DNA and prevents growth of AR-dependent cells (such as glandular epithelium in prostate).
  • the compound is Compound II.
  • the compound is Compound VI. P-4738-PC
  • the Compound 1-VI prevents recruiting co-repressors of androgen-responsive DNA and prevents growth of AR-dependent cells (such as glandular epithelium in prostate).
  • the compound is Compound II.
  • the compound is Compound VI.
  • the Compound I-VI prevents mitogenic action of Testosterone and DHT by blocking the ability of endogenous ligands to bind the receptor and induces the transcription of other hormones and growth factors which signal in a paracrine fashion to induce proliferation of prostate epithelium.
  • the compound is Compound II.
  • the compound is Compound VI.
  • the Compound I-VI prevents mitogenic action of Testosterone and DHT by blocking the ability of endogenous ligands to bind the receptor and induce downstream molecular signaling which induce programmed cell death of glandular epithelium.
  • the compound is Compound II.
  • the compound is Compound VI.
  • the present invention provides a safe and effective method of treating, preventing, suppressing, inhibiting or reducing the incidence of BPH and is particularly useful in treating male subjects suffering from symptoms and signs of BPH.
  • Figure 2 Effects of Compound VI on the size of prostate of seminal vesicles P-4738-PC and levator ani muscle in rats of varying hormonal status.
  • this invention provides a method of treating, preventing, suppressing, inhibiting or reducing the incidence of benign prostate hyperpiasia in a male subject, by administering to the subject a selective androgen receptor modulator (SARM).
  • the method includes administering an analog of the SARM.
  • the method includes administering a derivative of the SARM.
  • the method includes administering an isomer of the SARM.
  • the method includes administering a metabolite of the
  • the method includes administering a pharmaceutically acceptable salt of the SARM. In another embodiment, the method includes administering a hydrate of the SARM. In another embodiment, the method includes administering an N-oxide of the SARM. In another embodiment, the method includes administering a pharmaceutical product of the P-4738-PC SARM.
  • This invention provides in one embodiment a method of blocking the ability of DHT to induce hyperpiasia comprising contacting the Androgen Receptor with any one or more of Compound I-VI or a composition comprising any one or more of Compound I-VI , thereby blocking the ability of DHT to induce hyperpiasia.
  • the compound is Compound II.
  • the compound is Compound VI.
  • This invention provides in one embodiment a method of blocking the ability of DHT to induce hyperpiasia comprising contacting the Androgen Receptor with any one or more of Compound l-Vl or a composition comprising any one or more of Compound I-VI, thereby blocking the ability of DHT to induce hyperpiasia.
  • the compound is Compound II.
  • the compound is Compound VI.
  • Compound I-VI is a partial agonist and selective agonist that upon contact with the Androgen Receptor or by administration in a subject prevents mitogenic action of Testosterone and DHT by blocking the ability of endogenous ligands to bind to the receptor.
  • the compound is Compound II.
  • the compound is Compound VI.
  • the Compound I-VI prevents recruitment of co-activators or co-regulators of androgen-responsive DNA and prevents growth of AR- dependent cells (such as glandular epithelium in prostate).
  • the compound is Compound II.
  • the compound is Compound VI.
  • the Compound I-VI prevents recruiting co-repressors of androgen-responsive DNA and prevents growth of AR-dependent cells
  • the compound is P-4738-PC
  • the Compound l-Vl prevents mitogenic action of Testosterone and DHT by blocking the ability of endogenous ligands to bind the receptor and induces the transcription of other hormones and growth factors which signal in a paracrine fashion to induce proliferation of prostate epithelium.
  • the compound is Compound II.
  • the compound is Compound VI.
  • the Compound l-Vl prevents mitogenic action of Testosterone and DHT by blocking the ability of endogenous ligands to bind the receptor and induce downstream molecular signaling which induce programmed cell death of glandular epithelium.
  • the compound is Compound II.
  • the compound is Compound VI.
  • Compounds I-VI is a selective agonist in muscle and a partial agonist in prostate. Androgen action is mediated through the Androgen Receptor (AR).
  • AR is a ligand-dependent transcription factor that controls the expression of androgen-response genes by binding to androgen-response elements in DNA. Androgen-responsive genes are responsible for androgen- dependent proliferation and also androgen-dependent cell death. Also, other genes in cellular signaling cascades contribute to cellular proliferation or repression by signaling through the AR and in sequence with AR (upregulated by interaction with AR-dependent DNA, however, are mitogenic through alternative receptor involved in cellular proliferation (i.e. IGF-I).
  • Prostate is an androgen-sensitive tissue; thus Testosterone and DHT maintain normal structural and functional integrity of prostate (via AR).
  • T and DHT are also potent mitogens in prostate and can lead to abnormal growth of AR-dependent cells (such as prostatic glandular epithelial cells) with the ultimate consequence being prostatic disease like BPH and cancer.
  • Depletion of the androgenic support by P-4738-PC castration or inhibition of endogenous ligands for AR prevents the metabolic changes dependent on
  • Testosterone and DHT are Testosterone and DHT.
  • this invention also provides a method of treating a subject suffering from hair loss, comprising the step of administering to the subject a therapeutically effective amount of a 5- ⁇ reductase type 1 and/or type 2 enzyme inhibitor, wherein the inhibitor is a selective androgen receptor modulator (SARM).
  • the method includes administering an analog of the SARM.
  • the method includes administering a derivative of the SARM.
  • the method includes administering an isomer of the SARM.
  • the method includes administering a metabolite of the SARM.
  • the method includes administering a pharmaceutically acceptable salt of the SARM.
  • the method includes administering a hydrate of the SARM.
  • the method includes administering an N-oxide of the SARM.
  • this invention also provides a method of inhibiting a 5- ⁇ reductase type 1 and/or type 2 enzyme, comprising contacting the enzyme with an effective 5- ⁇ reductase inhibitory amount of a selective androgen receptor modulator (SARM).
  • the method includes administering an analog of the SARM.
  • the method includes administering a derivative of the SARM.
  • the method includes administering an isomer of the SARM.
  • the method includes administering a metabolite of the SARM.
  • the method includes administering a pharmaceutically acceptable salt of the SARM.
  • the method includes administering a hydrate of the SARM.
  • the method includes administering an N-oxide of the SARM.
  • SARMs are a class of androgen receptor targeting agents (ARTA), which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. These novel agents are useful in males and females for the treatment of a variety of hormone-related conditions, such as hypogonadism, sarcopenia, erythropoiesis, erectile dysfunction, lack of libido, osteoporesis and infertility. Further, SARMs are useful for oral testosterone replacement therapy, treating prostate cancer, imaging prostate cancer, and maintaining sexual desire in women.
  • ARTA androgen receptor targeting agents
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula I.
  • G is O or S
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR; • T is OH, OR, -NHCOCH3, or NHCOR
  • Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO 2 CH 3 , NHS0 2 R, OR, COR,
  • OCOR, OS0 2 R, S0 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2) CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
  • R 1 is CH 3 , CH 2 F, CHF 2l CF 3 , CH 2 CH 3 , or CF 2 CF 3 .
  • the SARM is an analog of the compound of formula I. In another embodiment, the SARM is a derivative of the compound of formula I. In another embodiment, the SARM is an isomer of the compound of formula I. In another embodiment, the SARM is a metabolite of the compound of formula I. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula I. In another embodiment, the SARM is a pharmaceutical product of the compound of formula I. In another embodiment, the SARM is a hydrate of the compound of formula I. In another embodiment, the SARM is an N-oxide of the compound of formula I. In another embodiment, the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula I.
  • the SARM compound is a compound of formula I wherein X is O. In one embodiment, the SARM compound is a compound of formula I wherein G is O. In another embodiment, the SARM compound is a compound of formula I wherein Z is N0 2 . In another embodiment, the SARM compound is a compound of formula I wherein Z is CN. In another embodiment, the SARM compound is a compound of formula I wherein Y is CF 3 . In another embodiment, the SARM compound is a compound of formula I wherein Q is NHCOCH 3 . In another embodiment, the SARM compound is a compound of formula I wherein Q is F. In another embodiment, the SARM compound is a compound of formula I wherein T is OH. In another embodiment, the SARM P-4738-PC compound is a compound of formula I wherein R ⁇ ,is CH3.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula II.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
  • Q is alkyl, halogen, CF 3 , CN CR 3) SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, OS0 2 R, S0 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH.
  • the SARM is an analog of the compound of formula P-4738-PC
  • the SARM is a derivative of the compound of formula
  • the SARM is an isomer of the compound of formula
  • the SARM is a metabolite of the compound of formula II.
  • the SARM is a pharmaceutically acceptable salt of the compound of formula II.
  • the SARM is a pharmaceutical product of the compound of formula II.
  • the SARM is a hydrate of the compound of formula II.
  • the SARM is an N-oxide of the compound of formula II.
  • the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula II.
  • the SARM compound is a compound of formula II wherein X is O. In another embodiment, the SARM compound is a compound of formula II wherein Z is N0 2 . In another embodiment, the SARM compound is a compound of formula II wherein Z is CN. In another embodiment, the SARM compound is a compound of formula II wherein Y is CF 3 . In another embodiment, the SARM compound is a compound of formula II wherein Q is NHCOCH 3 . In another embodiment, the SARM compound is a compound of formula II wherein Q is F.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula III.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
  • G is O or S
  • R- is CH 3 , CH 2 F, CHF 2 , CF 3l CH 2 CH 3 , or CF 2 CF 3 ;
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 ,
  • A is a ring selected from:
  • B is a ring selected from:
  • a and B cannot simultaneously be a benzene ring;
  • Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN CR 3 or SnR 3 ;
  • Qi and Q 2 are independently of each other a hydrogen, alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF3,
  • NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHS0 2 CH 3 , NHS0 2 R, OR, COR, OCOR,
  • Q 3 and Q 4 are independently of each other a hydrogen, alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF3, P-4738-PC
  • NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 ,
  • NHCSCFs NHCSR NHS0 2 CH 3l NHS0 2 R, OR, COR, OCOR,
  • Wi is O, NH, NR, NO or S; and W 2 is N or NO.
  • the SARM is an analog of the compound of formula 111. In another embodiment, the SARM is a derivative of the compound of formula III. In another embodiment, the SARM is an isomer of the compound of formula III. In another embodiment, the SARM is a metabolite of the compound of formula 111. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula III. In another embodiment, the SARM is a pharmaceutical product of the compound of formula III. In another embodiment, the SARM is a hydrate of the compound of formula III. In another embodiment, the SARM is an N-oxide of the compound of formula 111. In another embodiment, the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula III.
  • the SARM compound is a compound of formula III wherein X is O. In another embodiment, the SARM compound is a compound of formula III wherein G is O. In another embodiment, the SARM compound is a compound of formula I wherein T is OH. In another embodiment, the SARM compound is a compound of formula III wherein Ri is CH 3 . In another embodiment, the SARM compound is a compound of formula III wherein Z is N0 2 . In another embodiment, the SARM compound is a compound of formula III wherein Z is CN. In another embodiment, the SARM compound is a compound of formula III wherein Y is CF 3 . In another embodiment, the SARM compound is a compound of formula III wherein Qi is NHCOCH 3 . In another embodiment, the SARM compound is a compound of formula III wherein Qi is F. P-4738-PC
  • the substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter "A ring").
  • the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituents Qi and Q 2 can be in any position of the ring carrying these substituents (hereinafter "B ring").
  • the substitutent Qi is in the para position of the B ring.
  • the subsituent is Q 2 is H.
  • the substitutent Qi is in the para position of the B ring and the subsituent is Q 2 is H.
  • the substitutent Q-i is NHCOCH 3 and is in the para position of the B ring, and the substituent is Q 2 is H.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula IV.
  • X is a bond, O, CH 2 , NH, Se, PR, NO or NR; G is O or S;
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF3, aryl, phenyl, halogen, alkenyl or OH;
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3l or CF 2 CF 3 ; P-4738-PC
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, N0 2 , NHCOCH 3)
  • NHCOCFs NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, NR 2 , SR;
  • R 3 is F, Cl, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 ,
  • Z is N0 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 ⁇ F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 ,
  • NHCOCHs NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHS0 2 CH 3 , NHS0 2 R, OH, OR, COR, OCOR, OS0 2 R, S0 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • n is an integer of, 1-4; and m is an integer of 1-3.
  • the SARM is an analog of the compound of formula IV. In another embodiment, the SARM is a derivative of the compound of formula IV. In another embodiment, the SARM is an isomer of the compound of formula IV. In another embodiment, the SARM is a metabolite of the compound of formula IV. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula IV. In another embodiment, the SARM is a P-4738-PC pharmaceutical product of the compound of formula IV. In another embodiment, the SARM is a hydrate of the compound of formula IV. In another embodiment, the SARM is an N-oxide of the compound of formula IV. In another embodiment, the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula IV.
  • the SARM compound is a compound of formula IV wherein X is O. In another embodiment, the SARM compound is a compound of formula IV wherein G is O. In another embodiment, the SARM compound is a compound of formula IV wherein Z is N0 2 . In another embodiment, the SARM compound is a compound of formula IV wherein Z is CN. In another embodiment, the SARM compound is a compound of formula IV wherein Y is CF 3 . In another embodiment, the SARM compound is a compound of formula IV wherein Q is NHCOCH 3 . In another embodiment, the SARM compound is a compound of formula IV wherein Q is F. In another embodiment, the SARM compound is a compound of formula IV wherein T is OH.
  • the SARM compound is a compound of formula IV wherein R 1 is CH 3 . In another embodiment, the SARM compound is a compound of formula IV wherein Q is F and R 2 is CH 3 . In another embodiment, the SARM compound is a compound of formula IV wherein Q is F and R 2 is Cl.
  • the substituents Z, Y and R 3 can be in any position of the ring carrying these substituents (hereinafter "A ring").
  • a ring the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituents Q and R 2 can be in any position of the ring carrying these substituents (hereinafter "B ring").
  • the substitutent Q is P-4738-PC in the para position of the B ring.
  • the substitutent Q is in the para position of the B ring.
  • the substitutent Q is
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5D-reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula V.
  • R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, N0 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, NR 2 , SR;
  • R 3 is F, Cl, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 , SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; P-4738-PC
  • Z is N0 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or SnR 3 ;
  • Q is H, alkyl, halogen, CF 3 , CN CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3) NHCSR NHS0 2 CH 3 , NHSO 2 R, OH, OR, COR, OCOR, OS0 2 R, S0 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
  • the SARM is an analog of the compound of formula V. In another embodiment, the SARM is a derivative of the compound of formula
  • the SARM is an isomer of the compound of formula
  • the SARM is a metabolite of the compound of formula V.
  • the SARM is a pharmaceutically acceptable salt of the compound of formula V.
  • the SARM is a pharmaceutical product of the compound of formula V.
  • the SARM is a hydrate of the compound of formula V.
  • the SARM is an N-oxide of the compound of formula V.
  • the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula V.
  • the SARM is a compound of formula V wherein Z is N0 2 . In another embodiment, the SARM is a compound of formula V wherein Z is CN. In another embodiment, the SARM is a compound of formula V wherein P-4738-PC
  • the SARM is a compound of formula V wherein Q is NHCOCH 3 .
  • the SARM is a compound of formula V wherein Q is F.
  • the SARM is a compound of formula V wherein Q is F and R 2 is CH 3 .
  • the SARM is a compound of formula V wherein Q is F and R 2 is Cl.
  • the substituents Z, Y and R 3 can be in any position of the A ring, and he substituents Q and R 2 can be in any position of B ring, as discussed above for compound IV. Furthermore, as discussed above, when the integers m and n are greater than one, the substituents R 2 and R 3 are not limited to one particular substituent, and can be any combination of the substituents listed above.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula VI.
  • the SARM is an analog of the compound of formula VI. In another embodiment, the SARM is a derivative of the compound of formula VI. In another embodiment, the SARM is an isomer of the compound of formula VI. In another embodiment, the SARM is a metabolite of the compound of formula VI. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula VI. In another embodiment, the SARM is a pharmaceutical product of the compound of formula VI. In another embodiment, the SARM is a hydrate of the compound of formula VI. In another embodiment, the SARM is an N-oxide of the compound of formula VI. In P-4738-PC another embodiment, the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula VI.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula VII.
  • the SARM is an analog of the compound of formula VII. In another embodiment, the SARM is a derivative of the compound of formula VII. In another embodiment, the SARM is an isomer of the compound of formula VII. In another embodiment, the SARM is a metabolite of the compound of formula VII. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula VII. In another embodiment, the SARM is a pharmaceutical product of the compound of formula VII. In another embodiment, the SARM is a hydrate of the compound of formula VII. In another embodiment, the SARM is an N-oxide of the compound of formula VII. In another embodiment, the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula VII.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound P-4738-PC represented by the structure of formula VIII.
  • the SARM is an analog of the compound of formula VIII. In another embodiment, the SARM is a derivative of the compound of formula VIII. In another embodiment, the SARM is an isomer of the compound of formula VIII. In another embodiment, the SARM is a metabolite of the compound of formula VIII. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula VIII. In another embodiment, the SARM is a pharmaceutical product of the compound of formula VIII. In another embodiment, the SARM is a hydrate of the compound of formula VIII. In another embodiment, the SARM is an N-oxide of the compound of formula VIII. In another embodiment, the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula VIII.
  • the SARM which: a) treats, prevents, inhibits, or suppresses BPH; and/or b) treats hair loss; and/or c) inhibits 5 ⁇ -reductase enzyme; and/or d) antagonizes the androgen receptor is a compound represented by the structure of formula IX.
  • the SARM is an analog of the compound of formula IX. In another embodiment, the SARM is a derivative of the compound of formula IX. In another embodiment, the SARM is an isomer of the compound of formula IX. In another embodiment, the SARM is a metabolite of the compound of formula IX. In another embodiment, the SARM is a pharmaceutically acceptable salt of the compound of formula IX. In another embodiment, the SARM is a pharmaceutical product of the compound of formula IX. In another embodiment, the SARM is a hydrate of the compound of formula IX. In another embodiment, the SARM is an N-oxide of the compound of formula IX. In another embodiment, the SARM is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the compound of formula IX.
  • the substituent R in compounds (I) and (II) is defined herein as an alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH.
  • alkyl group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons.
  • the alkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
  • alkenyl refers to an unsaturated hydrocarbon, including straight chain, branched chain and cyclic groups having one or more double bond.
  • the alkenyl group may have one double bond, two double bonds, three P-4738-PC double bonds etc.
  • Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl etc.
  • the alkenyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
  • haloalkyl group refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I.
  • aryl group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl.
  • Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
  • a "hydroxyl” group refers to an OH group.
  • An “alkenyl” group refers to a group having at least one carbon to carbon double bond.
  • a halo group refers to F, Cl, Br or l.
  • arylalkyl refers to an alkyl bound to an aryl, wherein alkyl and aryl are as defined above.
  • An example of an arylalkyl group is a benzyl group.
  • this invention provides a method of treating, preventing, suppressing, inhibiting or reducing the incidence of benign prostate hyperpiasia in a male subject, by administering to the subject a selective androgen receptor modulator (SARM).
  • the method includes administering an analog of said SARM.
  • the method includes administering a derivative of said SARM.
  • the method includes administering an isomer of said SARM.
  • the method includes administering a metabolite of said
  • the method includes administering a pharmaceutically acceptable salt of said SARM. in another embodiment, the method includes administering a hydrate of said SARM. In another embodiment, the method includes administering an N-oxide of said SARM. In another embodiment, the method includes administering a pharmaceutical product of said SARM.
  • isomer includes, but is not limited to optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.
  • this invention encompasses the use of different optical isomers of the SARM compound.
  • the SARMs of the present invention contain at least one chiral center. Accordingly, the SARMs used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereroisomeric form, or any combination thereof, which form possesses properties useful in the treatment of BPH described herein.
  • the SARMs are the pure (R)-isomers. In another embodiment, the SARMs are the pure (S)-isomers.
  • the SARMs are a mixture of the (R) and the (S) isomers. In another embodiment, the SARMs are a racemic mixture comprising an equal amount of the (R) and the (S) isomers. It is well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). P-4738-PC
  • the invention includes pharmaceutically acceptable salts of amino- substituted compounds with organic and inorganic acids, for example, citric acid and hydrochloric acid.
  • the invention also includes N-oxides of the amino substituents of the compounds described herein.
  • Pharmaceutically acceptable salts can also be prepared from the phenolic compounds by treatment with inorganic bases, for example, sodium hydroxide.
  • esters of the phenolic compounds can be made with aliphatic and aromatic carboxylic acids, for example, acetic acid and benzoic acid esters.
  • This invention further includes derivatives ofthe SARM compounds.
  • derivatives includes but is not limited to ether derivatives, acid derivatives, amide derivatives, acid derivatives, ester derivatives and the likes.
  • this invention further includes hydrates of the SARM compounds.
  • hydrate includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
  • This invention further includes metabolites ofthe SARM compounds.
  • metabolites ofthe SARM compounds means any substance produced from another substance by metabolism or a metabolic process.
  • This invention further includes pharmaceutical products of the SARM compounds.
  • pharmaceutical product means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
  • the SARMs which are useful in preventing and treating BPH are classified as androgen receptor agonists (AR agonists) or androgen receptor antagonists (AR antagonists).
  • AR agonists androgen receptor agonists
  • AR antagonists androgen receptor antagonists
  • the AR is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous androgens (male sex hormones).
  • the androgenic hormones are steroids which are produced in the body by the testis and the cortex of the adrenal gland. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol. Met. Clin.
  • the endogenous steroidal androgens include testosterone and dihydrotestosterone ("DHT").
  • Other steroidal androgens include esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone ("MENT”') and its acetate ester (Sundaram et al., "7 Alpha-Methyl-Nortestosterone(MENT): The Optimal Androgen For Male Contraception," Ann. Med., 25:199-205 (1993) (“Sundaram”)).
  • a receptor agonist is a substance which binds receptors and activates them.
  • a receptor antagonist is a substance which binds receptors and inactivates them.
  • the SARMs which are useful in treating and preventing BPH are AR agonists, and are, therefore, useful in binding to and activating the AR.
  • the SARMs which are useful in treating and preventing BPH are AR antagonists, and are, therefore, useful in binding to and inactivating the AR.
  • Assays to determine whether the compounds of the present invention are AR agonists or antagonists are well known to a person skilled in the art.
  • AR agonistic activity can be determined by monitoring the ability of the SARM compounds to maintain and/or stimulate the growth of AR containing tissue such as prostate and seminal vesicles, as measured by weight.
  • AR antagonistic activity can be determined by monitoring the ability of the SARM compounds inhibit the growth of AR containing tissue.
  • the SARM compounds of the present invention can be classified as partial AR agonist/antagohists.
  • the SARMs are
  • AR agonists in some tissues, to cause increased transcription of AR-responsive genes (e.g. muscle anabolic effect).
  • these compounds serve as competitive inhibitors of testosterone/DHT on the AR to prevent agonistic effects of the native androgens.
  • the compounds of the present invention bind either reversibly or irreversibly to the androgen receptor.
  • the SARM compounds bind reversibly to the androgen receptor.
  • the SARM compounds bind irreversibly to the androgen receptor.
  • the compounds of the present invention may contain a functional group (affinity label) that allows alkylation of the androgen receptor (i.e. covalent bond formation).
  • the compounds bind irreversibly to the receptor and, accordingly, cannot be displaced by a steroid, such as the endogenous ligands DHT and testosterone.
  • the SARM compounds ofthe present invention are potent inhibitors of a 5- ⁇ reductase enzyme.
  • this invention provides a method of inhibiting a 5- ⁇ reductase enzyme, comprising contacting the enzyme with an effective 5- ⁇ reductase inhibitory amount of a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof, as described herein.
  • SARM selective androgen receptor modulator
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula I.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula II.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula III.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of P-4738-PC formula IV.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula V.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula VI.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula VII.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula VII.
  • SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula VIII.
  • the SARM compound that is shown to be a potent inhibitor of a 5- ⁇ reductase enzyme is a compound of formula IXI.
  • the 5- ⁇ reductase, enzyme is a testosterone 5- ⁇ reductase enzyme.
  • a testosterone 5- ⁇ reductase enzyme is an enzyme which converts testosterone (T) to dihydrotestosterone (DHT).
  • DHT which binds with five-fold greater affinity to the human androgen receptor, is thought to be the mediator of androgen effects in many tissues.
  • DHT causes proliferation ofthe prostatic tissue, and excessive DHT levels are accompanied by excessive cellular proliferation, which is in turn accompanied by prostate enlargement.
  • the formation of DHT could be curtailed and, it is hoped, prostate enlargement can be blocked.
  • the SARMs ofthe present invention are effective in inhibiting both type 1 and type 2 5- ⁇ reductase.
  • the SARM compound that is shown to be a potent inhibitor of 5- ⁇ reductase enzyme is potent inhibitor of 5- ⁇ reductase enzyme type 1.
  • the SARM compound that is shown to be a potent inhibitor of 5- ⁇ reductase enzyme is potent inhibitor of 5- ⁇ reductase enzyme type 2.
  • the SARM compound that is shown to be a potent inhibitor of 5- ⁇ reductase enzyme is a competitive inhibitor of the 5- ⁇ reductase enzyme.
  • contacting means that the SARM compound of the present invention is introduced into a sample containing the enzyme in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the SARM to the enzyme.
  • Methods for contacting the samples with the SARM or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.
  • the term "contacting" means that the SARM compound of the present invention is introduced into a subject receiving treatment, and the SARM compound is allowed to come in contact with the androgen receptor in-vivo.
  • the androgenic hormones such as testosterone and DHT play an important role in many physiologic processes, including the development and maintenance of the male hair pattern.
  • inhibition of 5- ⁇ reductase inhibitor by the SARM compounds of the present invention affects male hair loss.
  • This invention thus provides a method of treating a subject suffering from hair loss, comprising the step of administering to the subject a therapeutically effective amount of a 5- ⁇ reductase inhibitor, wherein said inhibitor is a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof as described herein.
  • SARM selective androgen receptor modulator
  • treating includes disorder remitative treatment.
  • This invention provides the use of a composition and a pharmaceutical composition for treating, preventing, suppressing, inhibiting or reducing the incidence of benign prostate hyperpiasia in a male subject, the composition comprising a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof as described herein, in a pharmaceutical preparation further comprising a suitable carrier or diluent.
  • SARM selective androgen receptor modulator
  • This invention further provides the use of a composition and a pharmaceutical composition for treating a subject suffering from hair loss, the composition comprising a therapeutically effective amount of a 5- ⁇ reductase inhibitor, wherein the inhibitor is a selective androgen receptor modulator (SARM) and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof as described herein.
  • SARM selective androgen receptor modulator
  • the present invention provides a safe and effective method for treating, preventing, suppressing, inhibiting or reducing BPH and is particularly useful for relieving symptoms and signs associated with BPH in a subject suffering from BPH.
  • the present invention further provides a safe and effective method for treating hair loss in a subject suffering from hair loss.
  • the subject is a mammalian subject.
  • the subject is a human subject.
  • the subject is a male subject.
  • pharmaceutical composition means a “therapeutically effective amount” of the active ingredient, i.e. the SARM compound, together with a pharmaceutically acceptable carrier or diluent.
  • a “therapeutically effective P-4738-PC amount” as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen.
  • compositions containing the SARM agent can be administered to a subject by any method known to a person skilled in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially, intravaginally or intratumorally.
  • the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation.
  • Suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like.
  • Suitable liquid oral formulations include solutions, suspensions, dispersions, emulstions, oils and the like.
  • the SARM compounds are formulated in a capsule.
  • the compositions of the present invention comprise in addition to the SARM active compound and the inert carrier or diluent, a hard gelating capsule.
  • the pharmaceutical compositions are administered by intravenous, intraarterial, or intramuscular injection of a liquid preparation.
  • suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration.
  • the pharmaceutical compositions are administered intraarterially, and are thus formulated in a form suitable for intraarterial administration.
  • the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration.
  • the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a form suitable for topical administration.
  • Suitable topical formulations include gels, ointments, creams, lotions, drops and the like.
  • the SARM agents or their physiologically tolerated derivatives such as salts, esters,
  • N-oxides, and the like are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • the pharmaceutical compositions are administered as a suppository, for example a rectal suppository or a urethral suppository. Further, in another embodiment, the pharmaceutical compositions are administered by subcutaneous implantation of a pellet. In a further embodiment, the pellet provides for controlled release of SARM agent over a period of time.
  • the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990);
  • carrier or diluents are well known to those skilled in the art.
  • the carrier or diluent may be a solid carrier or diluent for solid formuations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.
  • Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. P-4738-PC polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • a starch e.g. corn starch, pregeletanized starch
  • a sugar e.g., lactose, mannitol, sucrose, dextrose
  • a cellulosic material e.g. microcrystalline cellulose
  • an acrylate e.g. P-4738-PC polymethylacrylate
  • pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
  • Parenteral vehicles for subcutaneous, intravenous, intraarterial, or intramuscular injection
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
  • compositions may further comprise binders (e.g. acacia, comstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povido ⁇ e), disintegrating agents (e.g.
  • binders e.g. acacia, comstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povido ⁇ e
  • disintegrating agents e.g.
  • comstarch potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent P-4738-PC absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.
  • solubiiizing agents e.g., glycerol, polyethylene glycerol
  • anti-oxidants e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole
  • stabilizers e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose
  • viscosity increasing agents e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum
  • sweetners e.g. aspartame, citric acid
  • lubricants e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
  • lubricants e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate
  • flow-aids e.g. colloidal silicon dioxide
  • plasticizers e.g. diethyl phthalate, triethyl citrate
  • emulsifiers e.g.
  • the pharmaceutical compositions provided herein are controlled release compositions, i.e. compositions in which the SARM compound is released over a period of time after administration.
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils).
  • the composition is an immediate release composition, i.e. a composition in which all of the SARM compound is released immediately after administration.
  • the pharmaceutical composition can be delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudeket al., N. Engl. J. Med. 321 :574 (1989).
  • polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a P-4738-PC fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of
  • compositions may also include incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.)
  • polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • polymers e.g. poloxamers or poloxamines
  • Also comprehended by the invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline.
  • the modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al., 1981 ; Newmark et al., 1982; and Katre et al., 1987).
  • Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound.
  • the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound.
  • P-4738-PC The preparation of pharmaceutical compositions which contain an active component is well understood in the art, for example by mixing, granulating, or tablet-forming processes.
  • the active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient.
  • the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • additives customary for this purpose such as vehicles, stabilizers, or inert diluents
  • suitable forms for administration such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • the SARM agents or their physiologically tolerated derivatives such as salts, esters, N- oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other.
  • An active component can be formulated into the composition as
  • salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic
  • the salts of the SARM will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by P-4738-PC mixing a solution ofthe compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric
  • contacting means that the SARM compound of the present invention is introduced into a sample containing the enzyme in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the SARM to the enzyme.
  • Methods for contacting the samples with the SARM or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.
  • the term "contacting" means that the SARM compound of the present invention is introduced into a subject receiving treatment, and the SARM compound is allowed to come in contact with the androgen receptor in vivo.
  • the term “treating” includes preventative as well as disorder remitative treatment.
  • the terms “reducing”, “suppressing” and “inhibiting” have their commonly understood meaning of lessening or decreasing.
  • progression means increasing in scope or severity, advancing, growing or becoming worse.
  • recurrence means the return of a disease after a remission.
  • administering refers to bringing a subject in contact with a SARM compound of the present invention.
  • administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in cells or tissues of living organisms, for example humans.
  • P-4738-PC the present invention encompasses administering the compounds ofthe present invention to a subject.
  • the methods of the present invention comprise administering a SARM compound as the sole active ingredient.
  • methods or treating BPH as disclosed herein which comprise administering the SARM compounds in combination with one or more therapeutic agents.
  • agents include, but are not limited to: LHRH analogs, reversible antiandrogens, antiestrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, or agents acting through other nuclear hormone receptors.
  • the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an LHRH analog. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a reversible antiandrogen. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an antiestrogen. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an anticancer drug.
  • the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a 5-alpha reductase inhibitor. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an aromatase inhibitor. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in P-4738-PC combination with a progestin. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an agent acting through other nuclear hormone receptors.
  • Testosterone can be reduced by the enzyme 5 ⁇ -reductase to dihydrotestosterone (DHT).
  • DHT dihydrotestosterone binds with five-fold greater affinity to the human androgen receptor and is thought to be the mediator of androgen effects in many tissues.
  • Compound VI mimics the effects of testosterone in many in vitro and in vivo systems, Compound VI was tested to determine whether it interacts with 5 ⁇ -reductase. This study (1) determined if Compound VI is a substrate for 5 ⁇ -reductase, and (2) determined if Compound VI has any effects on the conversion of testosterone to DHT via 5 ⁇ -reductase.
  • COS1 American Type Culture Collection, Manassas, VA cells were plated in twelve-well plates at a density of 60,000 cells/well and transiently P-4738-PC transfected with expression vectors for human 5 ⁇ -reductase (obtained from Dr.
  • Testosterone and Compound VI concentrations in the incubate were determined by HPLC using a reversed-phase column ( ⁇ BondaPak C18, 3.9 * 300 mm, Waters Corporation, Milford, MA) and a mobile phase of 38% acetonitrile in deionized water at a flow rate of 1.5 ml/min. Analytes were detected by UV absorbance at 254nm. Calibration curves were prepared using the peak areas to calculate the concentration of testosterone or Compound VI in the incubate at the completion of the reaction. Cells were lysed after the reaction and the cellular supernatant used to determine ⁇ -galactosidase activity and ensure equal transfection efficiency between wells.
  • Testosterone (4 ⁇ M) was rapidly converted to DHT when incubated with 5 ⁇ - reductase type 1 or type 2, decreasing by 34% and 35%, respectively, in the presence of these enzymes.
  • the conversion of testosterone to DHT was inhibited by the presence of Compound VI, with less than 10% decreases in testosterone concentration being observed in the presence of Compound VI
  • Compound VI is not a substrate but acts as a competitive inhibitor of 5 ⁇ - reductase type 1 and type 2.
  • SARMs selective androgen receptor modulators
  • Compound VI is a potent and efficacious selective androgen receptor modulator (SARM) in castrated male rats.
  • SARM selective androgen receptor modulator
  • TP testosterone propionate
  • Sprague-Dawley rats weighing 187 to 214 were randomly distributed into 9 groups of 5 animals.
  • groups 4 through 6 and groups 7 through 9 received unilateral or bilateral orchidectomy, ' respectively, via a midline scrotal incision.
  • Groups 1 through 3 did not undergo surgery. All drugs given to animals were freshly prepared as solutions in polyethylene glycol 300 (PEG 300).
  • Groups 4 and 7 received treatment with vehicle alone (i.e., PEG 300).
  • Animals in groups 3, 6, and 9 received testosterone propionate (TP, 0.5 mg/day) via implantation of subdermal osmotic pumps (Model 2002, Durect Corporation, Palo Alto, CA).
  • the ventral prostates, seminal vesicles, and levator ani muscle were removed and weighed. Osmotic pumps were also removed from animals to check for correct pump operation. The weights of all organs were normalized to body weight, and analyzed for any statistically significant differences between groups using single-factor ANOVA with the alpha value set a priori at p ⁇ 0.05. The weights of prostates and seminal vesicles were used as indices for evaluation of androgenic activity, and the levator ani muscle weight was used to evaluate the anabolic activity. Statistical analyses of parameters from complete blood count or serum chemical profiling, wherever applicable, were performed by single-factor ANOVA with the alpha value set a priori at p ⁇ 0.05.
  • Compound VI has little to no effect on endogenous androgen production at pharmacologically relevant doses.
  • Control Compound VI TP (0.5mg/day)
  • Plasma FSH and LH levels significantly increased in animals that received bilateral orchidectomy (i.e., castrated controls). Plasma FSH levels and LH levels in hemi-orrissactomized animals were not significantly different than intact animals, corroborating the observation that unilateral orchidectomy had no effect on plasma testosterone levels or the pituitary hormones that regulate it. Treatment with TP caused a significant decrease in FSH and LH levels in castrated male rats, indicating that TP suppresses pituitary hormone production. However, Compound VI had no effect P-4738-PC on plasma FSH and LH levels. These data indicate that Compound VI has no effect on pituitary hormone production and is therefore advantageous to TP for use in intact animals. No significant differences in FSH or LH levels were observed in intact or hemi-orezectomized animals.
  • Control Compound VI TP (0.5mg/day) (0.5mg/day)
  • Control Compound VI TP (0.5mg/day) (0.5mg/day)
  • Osteocalcin is a specific osteoblastic marker that can be used to evaluate the endogenous bone formation rate. There were no significant differences in osteocalcin levels between intact, hemi-orommectomized and castrated animals in the vehicle-treated (i.e., control) animals. However, treatment with Compound VI led to a significant increase in plasma osteocalcin levels in hemi- orchidectomized and castrated animals. TP had no effect on plasma osteocalcin levels. These data demonstrate that Compound VI increases bone formation rate in male animals with no effects on plasma concentrations of testosterone, FSH. or LH.
  • Control Compound VI TP (0.5mg/day) (0.5mg/day)
  • Compound VI decreased the size ofthe prostate to 79% of that observed in control animals, with no statistically significant changes in the size o the seminal vesicles or levator ani muscle (Table 5 below and Figure 2).
  • the pharmacologic effects and tissue selectivity of Compound VI were more obvious in hemi-orommectomized animals.
  • Compound VI decreased the size of the prostate and seminal vesicles to 75% and 79%, respectively, and increased the size of the levator ani muscle to 108% of that observed in untreated hemi- P-4738-PC orchidectomized animals.
  • Compound VI demonstrated potent and tissue-selective pharmacologic effects in intact, hemi-orommectomized and castrated male rats.
  • Compound VI led to significant decreases in prostate weights in intact and hemi- orchidectomized animals, and was less effective than TP at increasing the weight of the prostate in castrated animals.
  • Similar pharmacologic effects were noted in the seminal vesicles (another organ generally considered as a marker of P-4738-PC androgenic effects), with the exception that Compound VI had no effect on the weight of the seminal vesicles in intact animals.
  • Compound VI treatment led to significant increases in the weight of the levator ani muscle in hemi- orchidectomized and castrated animals.
  • Compound II is a selective androgen receptor modulator (SARM) in castrated male rats. It behaved as an agonist in anabolic tissue while a partial agonist in androgenic tissue. When it's administered to intact male rats at the dose rate of 0.5 mg/day, Compound II significantly decreased the prostate weight to 63% of that observed in vehicle-treated intact animals without affecting the levator ani muscle weight.
  • the tissue selectivity Compound II demonstrated in intact male rats could be explained by two possible mechanisms; 1) in the presence of endogenous testosterone, Compound II simply behaved as a partial agonist in DHT-dependent androgenic tissue; 2) Compound II is also a 5 ⁇ - reductase inhibitor besides its partial agonist activity in androgenic tissues.
  • the intact male rats were treated with hydroxy-flutamide (0.5, 1 , 5, 10 or 25 mg/kg), finasteride (5 mg/kg), Compound II (0.5, 1 , 5, 10, 25mg/kg) or vehicle for
  • the drugs were dissolved in DMSO:PEG300 (20:80, v:v) and administered via daily subcutaneous injections, and the dosages were adjusted based on animal's body weight, which was measured on a daily basis.
  • the animals were sacrificed within 8 hours after the last dose, the androgenic and anabolic tissues (ventral prostate, seminal vesicle and levator ani muscle) were removed and weighed, the prostate was frozen and stored at -80 D C for analyzing tissue concentrations of DHT and testosterone, and blood samples were collected and used for the measurement of serum markers, including FSH, LH and testosterone.
  • the organ weights were normalized with the body weights. Percentage changes were determined by comparison to intact animals. Statistical analyses of all the parameters were performed by single-factor ANOVA with the alpha value set a priori at p ⁇ 0.05.
  • Figures 3 to 5 show the change in organ weights in all treatment groups after different treatment periods. Hydroxyflutamide at all doses (0.5, 1 , 5, 10, 25mg/kg), significantly decreased the wet weight ofthe prostate, seminal vesicle and levator ani muscle within three days of treatment. However, no typical dose-response relationship was observed in any of these organs. Similar in all the dose groups, the prostate, seminal vesicle and levator ani muscle were significantly decreased to approximately 60%, 50% and 85%, respectively. There was no significant difference between any two of these dose groups. At the same time point, castration significantly decreased the prostate, seminal vesicle and levator ani muscle to 45%, 30% and 71%, respectively.
  • Compound II treated groups no typical dose-response relationship was observed either, similar results were observed in most ofthe dose groups (0.5, 1 , 5, 10, 25mg/kg) after three days of treatment.
  • Compound II decreased the prostate and seminal vesicle weights to 80% and 70%, without P-4738-PC affecting the levator ani muscle weight.
  • finasteride 5mg/kg significantly decreased the prostate and seminal vesicle weight to 59% and 38%, while showing no effect on the levator ani muscle weight.
  • Compound II was also able to decrease the prostate and seminal vesicle weights in intact animals after 3, 6 or 9 days treatment, and no typical dose-response relationship was observed at 3 and 6 day time point, although some dose-dependent changes were seen at lower doses (0.5, 1 , 5mg/kg) after 9 days treatment.
  • Compound II did not significantly decrease the levator ani muscle weights at any of the doses after 3, 6 or 9 days treatment, 25mg/kg dose treatment even increased the levator ani muscle weight by 12% after 9 days treatment.
  • Compound II reduces prostate in intact Sprague-Dawley rats
  • Prostate weights (g) were normalized to body weight (g), and the results are shown in Figure 6.
  • Animals treated with 10 mg/kg of Compound II demonstrated a markedly decreased prostate-to-Body weight ratio of 0.62% relative to 0.128% in the 0 mg/kg control group (Group 1).
  • Compound II dramatically reduced the prostate weight (normalized to body weight) by greater than 48.4% when compared to the intact control (p ⁇ 0.01).
  • increasing the dose 100- fold above 10 mg/kg day did not significantly increase the atrophy in prostate (10 mg/kg compared to 1000 mg/kg).
  • the results demonstrate herein show that Compound II will be an effective intervention for reducing the size ofthe prostate and therefore minimizing the symptoms associated with benign prostate hyperpiasia at relatively low pharmacological doses.

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KR1020047012236A KR101032661B1 (ko) 2002-02-07 2003-02-06 선택적 안드로겐 수용체 조절자를 이용한 양성 전립선과형성증의 치료 방법
BRPI0307699-7A BRPI0307699A2 (pt) 2002-02-07 2003-02-06 Tratamento de hiperplasia benigna da próstata com sarms.
CN038078007A CN1646115B (zh) 2002-02-07 2003-02-06 Sarms在制备用于治疗良性前列腺增生的药物中的应用
AT03737647T ATE518537T1 (de) 2002-02-07 2003-02-06 Selective androgen-rezeptor-modulatoren (sarms) für die behandlung der benignen prostatahyperplasie
CA002475108A CA2475108A1 (en) 2002-02-07 2003-02-06 Treating benign prostate hyperplasia with sarms
EA200401043A EA013399B1 (ru) 2002-02-07 2003-02-06 Лечение доброкачественной гиперплазии простаты селективным модулятором рецептора андрогенов (sarm)
YU69704A RS69704A (en) 2002-02-07 2003-02-06 Treating bening prostate hyperplasia with sarms
DK03737647.2T DK1480634T3 (da) 2002-02-07 2003-02-06 Selektive androgenreceptormodulatorer (SARM) til behandling af benign prostatahyperplasi
EP03737647A EP1480634B1 (de) 2002-02-07 2003-02-06 Selective Androgen-Rezeptor-Modulatoren (SARMs) für die Behandlung der benignen Prostatahyperplasie
MXPA04007639A MXPA04007639A (es) 2002-02-07 2003-02-06 Tratamiento de hiperplasia benigna de la prostata con un modulador de receptor de androgeno selectivo (sarm).
JP2003565418A JP4677516B2 (ja) 2002-02-07 2003-02-06 Ｓａｒｍを用いた前立腺肥大症治療
AU2003216174A AU2003216174C1 (en) 2002-02-07 2003-02-06 Treating benign prostate hyperplasia with SARMs
IL163380A IL163380A (en) 2002-02-07 2004-08-05 Treating benign prostate hyperplasia with sarms
HR20040793A HRP20040793A2 (en) 2002-02-07 2004-09-01 Treating benign prostate hyperplasia with sarms
HK05101488.2A HK1068103A1 (en) 2002-02-07 2005-02-22 Selective androgen receptor modulators (sarms) for treating benign prostate hyperplasia
AU2009201084A AU2009201084A1 (en) 2002-02-07 2009-03-18 Treatment of hair loss with SARMs
IL202675A IL202675A (en) 2002-02-07 2009-12-10 Selective modulators of androgen receptor and their pharmacological compositions
HR20100067A HRP20100067A2 (hr) 2002-02-07 2010-04-15 Liječenje benigne hiperplazije prostate selektivnim modulatorima androgenih receptora

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EP2305636A1 (de) * 2002-10-16 2011-04-06 University of Tennessee Research Foundation Selektive Androgen-Rezeptor-Modulatoren und Verfahren zu ihrer Verwendung
EP1558565A4 (de) * 2002-10-16 2006-04-19 Univ Tennessee Res Foundation Halogenierte selektiveandrogenrezeptormodulatoren und verfahren zu deren anwendung
EP1558565A2 (de) * 2002-10-16 2005-08-03 University Of Tennessee Research Foundation Halogenierte selektiveandrogenrezeptormodulatoren und verfahren zu deren anwendung
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HRP20060036B1 (hr) * 2003-06-27 2014-04-25 Orion Corporation Derivati propionamida koji se koriste kao modulatori androgenih receptora
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EA012430B1 (ru) * 2003-06-27 2009-10-30 Орион Корпорейшн Производные пропионамида, полезные в качестве модуляторов андрогенных рецепторов
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EP1750694A2 (de) * 2004-05-20 2007-02-14 University of Tennessee Research Foundation Metaboliten aus selektiven androgenrezeptormodulatoren und verfahren zu ihrer verwendung
EP2289872A3 (de) * 2004-06-07 2013-01-09 University of Tennessee Research Foundation Selektive Androgen-Rezeptor-Modulatoren und derer medizinischen Verwendung
US9884038B2 (en) 2004-06-07 2018-02-06 University Of Tennessee Research Foundation Selective androgen receptor modulator and methods of use thereof
US10662148B2 (en) 2004-06-07 2020-05-26 University Of Tennessee Research Foundation Selective androgen receptor modulator and methods of use thereof
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US9278914B2 (en) 2004-06-07 2016-03-08 University Of Tennessee Research Foundation SARMs and method of use thereof
EP1753417A4 (de) * 2004-06-07 2008-07-09 Univ Tennessee Res Foundation Selektive androgen-rezeptor-modulatoren und anwendungsverfahren dafür
US7670613B2 (en) 2004-07-08 2010-03-02 Pfizer Inc. Androgen modulators
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US9950125B2 (en) 2012-04-06 2018-04-24 Antares Pharma, Inc. Needle assisted jet injection administration of testosterone compositions
US10821072B2 (en) 2012-04-06 2020-11-03 Antares Pharma, Inc. Needle assisted jet injection administration of testosterone compositions
US11771646B2 (en) 2012-04-06 2023-10-03 Antares Pharma, Inc. Needle assisted jet injection administration of testosterone compositions
US9969683B2 (en) 2012-07-13 2018-05-15 Gtx, Inc. Method of treating estrogen receptor (ER)-positive breast cancers with selective androgen receptor modulator (SARMS)
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US10258596B2 (en) 2012-07-13 2019-04-16 Gtx, Inc. Method of treating HER2-positive breast cancers with selective androgen receptor modulators (SARMS)
US9744149B2 (en) 2012-07-13 2017-08-29 Gtx, Inc. Method of treating androgen receptor (AR)-positive breast cancers with selective androgen receptor modulator (SARMs)
US10849873B2 (en) 2012-07-13 2020-12-01 Oncternal Therapeutics, Inc Non-invasive method of evaluating breast cancers for selective androgen receptor modulator (SARM) therapy
US10987334B2 (en) 2012-07-13 2021-04-27 University Of Tennessee Research Foundation Method of treating ER mutant expressing breast cancers with selective androgen receptor modulators (SARMs)
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BRPI0307699A2 (pt) 2015-06-16
IL163380A (en) 2010-06-30
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EA013399B1 (ru) 2010-04-30
TWI374737B (en) 2012-10-21
AU2009201084A1 (en) 2009-04-09
GEP20074122B (en) 2007-06-11
CN1646115B (zh) 2010-06-09
AU2003216174B2 (en) 2008-12-18
CY1111917T1 (el) 2015-11-04
IL202675A (en) 2011-06-30
TW200918043A (en) 2009-05-01
MXPA04007639A (es) 2005-07-13
CA2689080A1 (en) 2003-08-14
CN101732298A (zh) 2010-06-16
CA2689080C (en) 2011-07-05
PT1480634E (pt) 2011-10-12
CN101732298B (zh) 2012-09-19
KR20100112659A (ko) 2010-10-19
HRP20100067A2 (hr) 2010-04-30
AU2003216174B8 (en) 2009-01-15
TW200307537A (en) 2003-12-16
HK1068103A1 (en) 2005-04-22
RS69704A (en) 2006-12-15
EP1480634A2 (de) 2004-12-01
ATE518537T1 (de) 2011-08-15
WO2003065992A3 (en) 2004-02-26
JP2010209102A (ja) 2010-09-24
US20100280107A1 (en) 2010-11-04
EP1480634A4 (de) 2008-01-16
EP1480634B1 (de) 2011-08-03
HRP20040793A2 (en) 2006-10-31
DK1480634T3 (da) 2011-11-14
KR101032661B1 (ko) 2011-05-06
KR20040089606A (ko) 2004-10-21
CN1646115A (zh) 2005-07-27
AU2003216174A1 (en) 2003-09-02
JP2013144713A (ja) 2013-07-25
JP2005522431A (ja) 2005-07-28
CA2475108A1 (en) 2003-08-14
US8088828B2 (en) 2012-01-03

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